Oncology is a branch of medicine that deals with cancer patients mainly parenterally (intravenously) rather than with oral drugs. During the past decade, there has been an increase in the treatment using parenteral drugs while little progress has been made in the oral drug therapy. Currently, more than 20 cytotoxic oral anticancer drugs are known. Most of the developed oral drugs were developed from previously known parenteral ones.
Some of the oral anticancer drugs were approved recently and others are studied consistently. The oral drug therapy is advantageous in terms of convenience and easiness of administration. With the acceleration in the development of oral drugs, the oral drug therapy is also expected to develop fast as well.
For taxane-based anticancer drugs, there has been an attempt to administer the P-glycoprotein inhibitor together in order to improve bioavailability for oral administration and many studies are under way in order to allow for oral administration of taxane drugs.
5-Fluorouracil (5-FU), which is commonly used in the treatment of gastrointestinal cancers including stomach cancer, is not suitable for oral administration because of low bioavailability and is known to induce side effects such as diarrhea. Capecitabine is an orally-administered chemotherapeutic agent. It is a prodrug that is enzymatically converted to 5-fluorouracil in the tumor. Capecitabine exhibits toxicity comparable to that of intravenously-administered 5-fluorouracil and is approved globally for use in breast cancer and colon cancer and is a successful case of oral anticancer drug development (V J O'Neil and C J Twelves, British Journal of Cancer (2002) 87: 933-937).
Among platinum-based anticancer drugs including oxaliplatin, satraplatin is the first and only orally-administered platinum-based chemotherapeutic drug.
Thousands of platinum complex derivatives have been synthesized and tested in preclinical phases, but only about 30 of them have entered into the clinical phase (Lloyd R Kelland, Expert Opinion on Investigational Drugs (2000) 9(6): 1373-1382). Currently, only 3 of them, i.e., cisplatin, carboplatin and oxaliplatin, are approved by the USFDA and are used in the form of injection (Hak Choy et al., Clin. Cancer Res. (2008) 14(6): 1633-1638).
Oxaliplatin is an organic complex consisting of platinum and 1,2-diaminocyclohexane and having an oxalate ligand as a leaving group. Its IUPAC name is (R,R)-1,2-diaminocyclohexane(ethanedioato-O,O)platinum. Currently, oxaliplatin is marketed for treatment of advanced colorectal cancer and metastatic stomach cancer under the brand name Eloxatin®. Frequently, it is administered together with 5-fluorouracil or leucovorin.
Metastatic colon cancer is treated by chemotherapy using Eloxatin® (oxaliplatin), FOLFOX (fluorouracil/leucovorin/oxaliplatin) or FOLFIRI (fluorouracil/leucovorin), and Genentech/Roche's Avastin® (bevacizumb) was approved in 2004 by the USFDA.
Oxaliplatin is administered only as injection and Eloxatin®, which is in a lyophilized form, needs to be diluted with water for Injection or glucose solution before its administration to a patient. The lyophilization process is complicated, costly and requires reconstitution. During the reconstitution, problems such as loss of oxaliplatin, precipitation, formation of undesirable particles, pollution, etc. may occur. Especially, the problem of pollution is of great importance when considering the toxicity of the antitumor substance.
Liquid formulation for injection is marketed recently in order to improve the inconvenience and problem of the lyophilized oxaliplatin for injection, but attempt to prepare oxaliplatin into orally-administrable form is not known yet.
Although satraplatin was first developed as orally-administered platinum-based drug and reported in 1993, it has not yet received approval from the USFDA for treatment of prostate cancer (In-Sung Park, Recent Trends in KOTRA (2007)).
Although the reason why oxaliplatin can be used only in the form of injection was not reported in detail, it was revealed from clinical tests that cisplatin and carboplatin, which are both platinum(II) complexes like oxaliplatin, exhibit very low bioavailability in the gastrointestinal tract when administered orally (Lloyd R Kelland, Expert Opinion on Investigational Drugs (2000) 9(6): 1373-1382).
Satraplatin is a platinum(IV)-based oral drug developed to solve the low bioavailability of the platinum(II) compound. Recently, the result of clinical trial phase III was reported for the compound (Hak Choy et al., Clin. Cancer Res. (2008) 14(6): 1633-1638).
Although the necessity of the development of orally-administrable anticancer drugs and their many advantages over injections are well understood, a number of restrictions including low bioavailability slow development thereof.
As for oxaliplatin, attempts have been made to prepare a stable aqueous solution of oxaliplatin to improve the aforesaid problems. U.S. Pat. No. 5,716,988 discloses a preparation of oxaliplatin for parenteral administration comprising an aqueous solution of oxaliplatin, in a concentration of 1-5 mg/mL, and with a pH in the range of 4.5-6. And, U.S. Pat. Nos. 6,476,068 and 6,306,902 disclose a pharmaceutically stable solution formulation comprising oxaliplatin and a method for preparing the same. Korean Patent No. 367,752 discloses a stably lyophilized pharmaceutical composition, Korean Patent No. 913,063 discloses a readily-usable injection solution containing oxaliplatin, and International Patent No. WO/2005/020980 discloses an oxaliplatin formulation for parenteral administration. In addition, US Patent Application Publication Nos. 2003-0109515 and 2004-0127557 disclose methods for preparing more stable composition, and Korean Patent Application Publication No. 10-2007-0067768 discloses a method for preparing a stable oxaliplatin composition with minimized toxicity of oxaliplatin.
Meanwhile, U.S. Pat. No. 7,217,735 discloses a pharmaceutical composition for oral administration comprising nanoparticles of hardly soluble paclitaxel. However, since the solvents described in the specification cannot dissolve water-soluble active substances such as oxaliplatin, the patent is inapplicable to preparation of nanoparticles of the water-soluble active substances.
At present, nanotechnology is used to dissolve drugs which have good physiological activities but are hardly soluble in aqueous solutions. Also, the technology allows for improvement of bioavailability by enhancing drug stability or maintenance of drug concentration in blood by controlling release rate. The drug stabilization using the nanotechnology contributes to the improvement of bioavailability and maintenance of long-term efficacy of such drugs as paclitaxel, docetaxel, doxorubicin, etc. which have the problems of solubility and stability (KIPO, 2006 Patent Litigation Map Project—Development of Nanopharmaceuticals (2006)).
However, although studies have been made on improved composition types and preparation thereof, nanoparticularization of hardly soluble active substances, or the like for parenteral administration of oxaliplatin, no orally administrable formulation comprising oxaliplatin only has been developed yet.